The overall aim of the project is to elucidate the genetic factors which determine (or influence) human immune responsiveness. This study is unique in that we are studying human immune response toward several ultra-pure pollen allergens in an epidemiologically defined population, as well as allergy patients and the consanguineous Amish population. We are studying both unrelated subjects and families. An important aspect of the work is a longitudinal study of the variation in phenotypic expression of responsiveness within an individual. Only with this knowledge is it possible to investigate definitively the role of genetic factors, including hypothesized immune response (Ir) and immune suppression (Is) genes, in determining human immune responsiveness and allergy. Segregation and linkage analysis will be performed to test for the presence of major genes, especially in relation to total IgE and specific IgE and IgG antibody production. An important aspect of our work is the studies of the mechanisms of immune supression using in vitro culture techniques, and taking advantage of the availability of unique HLA haplotypes from the Amish population. This project is the first such rigorously designed investigation of the genetics of immune response in man, which serves as a model for studying human immune responsiveness toward complex antigens under conditions of naturally limiting low dosage exposure.